Polyamine modulation of NMDARs as a mechanism to reduce effects of alcohol dependence.

Polyamine modulation of NMDARs as a mechanism to reduce effects of alcohol dependence. Recent Pat CNS Drug Discov. 2012 Aug;7(2):129-44 Authors: Barron S, Lewis B, Wellmann K, Carter M, Farook J, Ring J, Rogers DT, Holley R, Crooks P, Littleton J Abstract Relapse and neurodegeneration are two of the major therapeutic targets in alcoholism. Fortuitously, the roles of glutamate/NMDA receptors (NMDARs) in withdrawal, conditioning and neurotoxicity mean that NMDAR inhibitors are potentially valuable for both targets. Preclinical studies further suggest that inhibitory modulators that specifically reduce the co-agonist effects of polyamines on NMDARs are potential non-toxic medications. Using agmatine as a lead compound, over 1000 novel compounds based loosely on this structure were synthesized using feedback from a molecular screen. A novel series of aryliminoguanidines with appropriate NMDAR activity in the molecular screen were discovered (US patent application filed 2007). The most potent and selective aryliminoguanidine, JR 220 [4- (chlorobenzylidenamino)- guanidine hydrochloride], has now been tested in a screening hierarchy for anti-relapse and neuroprotective activity, ranging from cell-based assay, through tissue culture to animal behavior. This hierarchy has been validated using drugs with known, or potential, clinical value at these targets (acamprosate (N-acetyl homotaurine), memantine and topiramate). JR220 was non-toxic and ...
Source: Recent Patents on CNS Drug Discovery - Category: Drugs & Pharmacology Tags: Recent Pat CNS Drug Discov Source Type: research